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This study assessed the quality of life (QOL) and the functional outcome in daily living in patients with a chronic, treatment-resistant periprosthetic joint infection (PJI) or osteomyelitis, living with a natural or iatrogenic sinus tract. Methods: A follow-up examination in three national reference centers for septic bone and joint surgery was performed utilizing the Hospital Anxiety and Depression Scale (HADS-D/A), the Visual Analogue Scale (VAS), and the Short Form-36 (SF-36) score, including patients with a chronic sinus tract due to treatment-resistant PJI or osteomyelitis. Results: In total, 48 patients were included, with a mean follow-up time of 43.1 ± 23.9 months. The mean SF-36 Mental Component Summary (MCS) was 50.2 (±12.3) and the Physical Component Summary (PCS) was 33.9 (±11.3). The mean HADS-D was 6.6 (±4.4) and HADS-A was 6.2 (±4.6), and the VAS was 3.4 (±2.6). The SF-36 MCS showed no significant differences between the study group and the standard population (47.0, p = 0.10), as well as the HADS-A. The PCS in the study population was significantly worse (50.0, p < 0.001), as was the HADS-D. Conclusions: A sinus tract represents a treatment option in selected cases with an acceptable QOL. The treatment should be considered for multimorbid patients with a high perioperative risk or if the bone or soft tissue quality prevents surgery. [ABSTRACT FROM AUTHOR]

Data on reconstruction of the femoral anteversion (FA) and the center of rotation after total hip arthroplasty (THA) are rare. We aimed to answer whether a short-stem fixation enables improved anatomical reconstruction of the FA compared to a straight-stem. Methods: One hundred and thirty patients who underwent short- (n = 89, group A, prospective) or straight-stem THA (n = 41, group B, retrospective) were included. CT scans of the hip, knee, and ankle were performed pre- and postoperatively in group A and in group B during the last follow-up. Femoral torsion was determined using three-dimensional models. Results: The mean preoperative FA was 22.4° ± 11.0°, and the mean postoperative FA was 23.4° ± 10.1°. The relative difference was −0.8° ± 8°, and the absolute difference was 6.4° ± 4.9°. Gender analysis revealed significant differences in preoperative FA between female (f) and male (m) patients (28.1° ± 11.2° (f) vs. 18.4° ± 8.3° (m); p > 0.001) as well as in postoperative FA (26.7° ± 23.5° (f) vs. 21.0° ± 9.7° (m); p < 0.007) in group A. Postoperative FA was higher in group A (mean 6.8°; 23.9° ± 10.1° (f) vs. 16.6° ± 8.6° (m); p < 0.001). Conclusions: The study's findings suggest that short-stem THA leads to improved anatomical FA reconstruction; however, a substantial postoperative gender-related FA difference was detectable, which may warrant consideration by surgeons when determining the final stem anteversion. It should be noted that the impact of the postoperative gender-related FA difference on clinical outcomes is not entirely clear, and further research is warranted to elucidate this relationship. [ABSTRACT FROM AUTHOR]

• CRISP prospectively collected real-world data on advanced NSCLC and KRAS mutations. • Of 1039 patients, 39.5 % had KRAS mutations, 38.9 % of these were KRAS G12C-mutated. • KRAS G12C-mutated advanced NSCLC has poor outcome under current standard therapy. • Valuable historical control for upcoming clinical studies on KRAS -inhibitors. After decades of unsuccessful efforts in inhibiting KRAS, promising clinical data targeting the mutation subtype G12C emerge. Since little is known about outcome with standard treatment of patients with G12C mutated non-small cell lung cancer (NSCLC), we analyzed a large, representative, real-world cohort from Germany. A total of 1039 patients with advanced KRAS -mutant or -wildtype NSCLC without druggable alterations have been recruited in the prospective, observational registry CRISP from 12/2015 to 06/2019 by 98 centers in Germany. Details on treatment, best response, and outcome were analyzed for patients with KRAS wildtype, G12C, and non-G12C mutations. Within the study population, 160 (15.4 %) patients presented with KRAS G12C, 251 (24.2 %) with non-G12C mutations, 628 (60.4 %) with KRAS wildtype. High PD-L1 expression (Tumor Proportion Score, TPS > 50 %) was documented for 28.0 %, 43.5 %, and 28.9 % (wildtype, G12C, non-G12C) of the tested patients; 68.8 %, 89.3 %, and 87.7 % of the patients received first-line treatment combined with an immune checkpoint-inhibitor in 2019. TPS > 50 % vs. TPS < 1 % was associated with a significantly decreased risk of mortality in a multivariate Cox model (HR 0.39, 95 % CI 0.26−0.60, p =<0.001). There were no differences in clinical outcome between KRAS wildtype, G12C or non-G12C mutations and KRAS mutational status was not prognostic in the model. Here we describe the so far largest prospectively recruited cohort of patients with advanced NSCLC and KRAS mutations, with special focus on the G12C mutation. These data constitute an extremely valuable historical control for upcoming clinical studies that employ KRAS inhibitors. [ABSTRACT FROM AUTHOR]

CV9201 is an RNActive®-based cancer immunotherapy encoding five non-small cell lung cancer-antigens: New York esophageal squamous cell carcinoma-1, melanoma antigen family C1/C2, survivin, and trophoblast glycoprotein. In a phase I/IIa dose-escalation trial, 46 patients with locally advanced (n = 7) or metastatic (n = 39) NSCLC and at least stable disease after first-line treatment received five intradermal CV9201 injections (400–1600 µg of mRNA). The primary objective of the trial was to assess safety. Secondary objectives included assessment of antibody and ex vivo T cell responses against the five antigens, and changes in immune cell populations. All CV9201 dose levels were well-tolerated and the recommended dose for phase IIa was 1600 µg. Most AEs were mild-to-moderate injection site reactions and flu-like symptoms. Three (7%) patients had grade 3 related AEs. No related grade 4/5 or related serious AEs occurred. In phase IIa, antigen-specific immune responses against ≥ 1 antigen were detected in 63% of evaluable patients after treatment. The frequency of activated IgD+CD38hi B cells increased > twofold in 18/30 (60%) evaluable patients. 9/29 (31%) evaluable patients in phase IIa had stable disease and 20/29 (69%) had progressive disease. Median progression-free and overall survival were 5.0 months (95% CI 1.8–6.3) and 10.8 months (8.1–16.7) from first administration, respectively. Two- and 3-year survival rates were 26.7% and 20.7%, respectively. CV9201 was well-tolerated and immune responses could be detected after treatment supporting further clinical investigation. [ABSTRACT FROM AUTHOR]

Objectives In the AURA3 trial, individuals received osimertinib 80 mg once daily or chemotherapy for advanced non-small cell lung cancer. Here, we explore patient-reported symptoms possibly related to treatment. Materials and methods AURA3 was an open-label, randomized phase III trial involving 419 patients. As part of the trial’s exploratory objectives, individuals were asked to complete the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) electronically, first weekly for 18 weeks and then every 3 weeks for up to 57 weeks, subject to the availability of validated local-language versions (English, German, Japanese and Spanish versions were available). Results In total, 161 patients (38%; 102 receiving osimertinib, 59 receiving chemotherapy) provided data for PRO-CTCAE analyses (mean age: 64 years; 63% women). Diarrhea was reported more commonly with osimertinib than with chemotherapy, and was mostly graded as occurring rarely or occasionally. Decreased appetite was reported less commonly with osimertinib than with chemotherapy. The proportion of patients reporting nausea changed little from baseline with osimertinib and increased with chemotherapy. Few patients reported vomiting. Both nausea and vomiting were generally graded as mild in severity. Fatigue was reported less commonly with osimertinib than with chemotherapy, and was mostly graded as mild or moderate. Of patients reporting fatigue, the proportion grading it as interfering at least ‘somewhat’ with their usual or daily activities was lower with osimertinib than with chemotherapy. Conclusion Symptoms were generally mild and not frequent, with some differences in symptom patterns between the two treatment groups. The results support and complement the AURA3 trial data and give insight into patients’ experience with treatment. [ABSTRACT FROM AUTHOR]

Background: Advanced non-small cell lung cancer (NSCLC) represents a significant unmet medical need. Despite advances with targeted therapies in a small subset of patients, fewer than 20% of patients survive for more than two years after diagnosis. Cancer vaccines are a promising therapeutic approach that offers the potential for durable responses through the engagement of the patient's own immune system. CV9202 is a self-adjuvanting mRNA vaccine that targets six antigens commonly expressed in NSCLC (NY-ESO-1, MAGEC1, MAGEC2, 5 T4, survivin, and MUC1). Methods/Design: The trial will assess the safety and tolerability of CV9202 vaccination combined with local radiation designed to enhance immune responses and will include patients with stage IV NSCLC and a response or stable disease after first-line chemotherapy or therapy with an EGFR tyrosine kinase inhibitor. Three histological and molecular subtypes of NSCLC will be investigated (squamous and non-squamous cell with/without EGFR mutations). All patients will receive two initial vaccinations with CV9202 prior to local radiotherapy (5 GY per day for four successive days) followed by further vaccinations until disease progression. The primary endpoint of the study is the number of patients experiencing Grade >3 treatment-related adverse events. Pharmacodynamic analyses include the assessment of immune responses to the antigens encoded by CV9202 and others not included in the panel (antigen spreading) and standard efficacy assessments. Discussion: RNActive self-adjuvanted mRNA vaccines offer the potential for simultaneously inducing immune responses to a wide panel of antigens commonly expressed in tumors. This trial will assess the feasibility of this approach in combination with local radiotherapy in NSCLC patients. [ABSTRACT FROM AUTHOR]

Using inequalities of Rosser and Schoenfeld, we complete the first author's partial proof of exact formulas for the prime-counting function π(x) and the nth prime number pn. Only the four arithmetic operations and the floor function are involved in the formulas. We indicate how to modify them in order to accelerate their computation. [ABSTRACT FROM AUTHOR]

Catumaxomab is a trifunctional monoclonal antibody with binding sites directed to human EpCAM and the human T cell antigen CD3 (anti-EpCAM × anti-CD3). Catumaxomab demonstrated efficacy when administered intraperitoneally in patients with EpCAM positive malignant ascites from ovarian cancer in terms of tumor cell killing and reduction of ascites generation. As EpCAM is also overexpressed in NSCLC, the present study was conducted in order to evaluate safety and tolerability of intravenous treatment with catumaxomab. UICC stage IB–IV NSCLC patients were eligible, if they had at least one prior therapy. Other inclusion criteria were: age 18–75 years, adequate bone marrow function and AST or gamma-GT ≤ 2.5 ULN. Escalating doses of catumaxomab were administered over 8 h as a continuous intravenous infusion. Dose escalation started at 2 μg and was increased to 7.5 μg. In addition various doses of dexamethasone as premedication were investigated. All patients were pretreated with antihistamines. Dose limiting toxicity (DLT) was a grade 3 and 4 elevation of ALT, AST and gamma-GT, which was observed in dose level IV (10 mg dexamethasone premedication, 5 μg catumaxomab) and V (40 mg dexamethasone followed by 7.5 μg catumaxomab). Elevated liver enzymes decreased to grade 2 within 3–7 days and were at baseline level within 14 days after infusion. The maximum tolerated dose (MTD) was defined in dose level III (40 mg of dexamethasone followed by 5 μg of catumaxomab). Five micrograms of catumaxomab with a pre-medication of 40 mg dexamethasone and antihistamines can be recommended as first dose for i.v. therapy consisting of multiple catumaxomab infusions for patients with NSCLC. [ABSTRACT FROM AUTHOR]

Purpose: Superagers are older adults presenting excellent memory performance that may reflect resilience to the conventional pathways of aging. Our contribution aims to shape the evidence body of the known distinctive biomarkers of superagers and their connections with the Brain and Cognitive Reserve and Brain Maintenance concepts. Methods: We performed a systematic literature search in PubMed and ScienceDirect with no limit on publication date for studies that evaluated potential biomarkers in superagers classified by validated neuropsychological tests. Methodological quality was assessed using the QUADAS-2 tool. Results: Twenty-one studies were included, the majority in neuroimaging, followed by histological, genetic, cognition, and a single one on blood plasma analysis. Superagers exhibited specific regions of cortical preservation, rather than global cortical maintenance, standing out the anterior cingulate and hippocampus regions. Both superagers and controls showed similar levels of amyloid deposition. Moreover, the functional oscillation patterns in superagers resembled those described in young adults. Most of the quality assessment for the included studies showed medium risks of bias. Conclusion: This systematic review supports selective cortical preservation in superagers, comprehending regions of the default mode, and salience networks, overlapped by stronger functional connectivity. In this context, the anterior cingulate cortex is highlighted as an imaging and histologic signature of these subjects. Besides, the biomarkers included pointed out that the Brain and Cognitive Reserve and Brain Maintenance concepts are independent and complementary in the superagers' setting. [ABSTRACT FROM AUTHOR]

Up to 20% of total knee arthroplasty (TKA) patients continue to experience chronic postsurgical pain. Various factors have been identified as potential contributors, including so-called "yellow flags", encompassing symptoms of depression, anxiety, and catastrophizing, which were examined in this study to assess their predictive value concerning functional outcomes after TKA. Methods: Fifty TKA patients were categorized into high-risk and low-risk groups based on clinical assessment, demographic data, medication, and patient-reported outcome measures (DN4, SF-36, WOMAC, NRS, Fibromyalgia Survey Questionnaire, Pain Catastrophizing Scale, and Hospital Anxiety and Depression Scale). Postoperative outcomes within six months after TKA were then compared. Results: Both groups exhibited significant (p < 0.001) improvements in all WOMAC and NRS subscales, as well as in the physical function, role physical, pain, and energy/fatigue subdomains of the SF-36 after six months, while the high-risk group showed lower WOMAC scores regarding stiffness (19.0 ± 18.3 vs. 27.2 ± 20.7, p < 0.001) and pain (13.5 ± 13.3 vs. 15.1 ± 16.3, p = 0.029). The high-risk group showed significantly worse preoperative DN4 scores (1.8 ± 1.3 vs. 3.0 ± 1.1, p = 0.002) than the low-risk group, which persisted for one day (2.3 ± 1.2 vs. 3.5 ± 1.5, p = 0.005) and six weeks (2.2 ± 1.9 vs. 3.6 ± 2.3, p = 0.041) postoperatively. Conclusions: Our results indicate that pre-existing yellow flags contribute to a more challenging early postoperative phase, underscoring the importance of considering individual patient characteristics and psychological factors to optimize TKA outcomes. [ABSTRACT FROM AUTHOR]

Background Neoadjuvant immunochemotherapy is currently being tested in pivotal trials for stage I to III nonsmall cell lung cancer (NSCLC). The impact of immunochemotherapy in patients with oligometastatic disease (OMD) remains undefined. This study aimed to compare the outcomes of radical treatment after the neoadjuvant course of immunochemotherapy versus chemotherapy. Methods We retrospectively analyzed patients with OMD who were treated with immunochemotherapy or chemotherapy combined with local ablation of metastases and radical primary tumor resection between 2017 and 2021. Group A included eight patients with immunochemotherapy; Group B included seven patients with chemotherapy. Descriptive statistical analysis included the characteristics of the patients, tumors, and outcomes. Results There was no difference in postoperative morbidity rates between the groups (p = 0.626). The 30-day mortality in both groups was 0%. The median overall survival for Group A was not reached, with a median follow-up time of 25 (range: 13–35) months; the median overall survival for Group B was 26 (range: 5–53) months. In Group A, all patients remained alive; in contrast, in Group B, four patients died (p = 0.026). There was no local thoracic recurrence in either group. In Group B, the recurrent disease was identified significantly more often (12.5 vs. 85.75%; p = 0.009). The rates of complete and major pathologic response were 37.5 and 0% in Group A and 42.85 and 14.25% in Group B, respectively. Conclusion Despite the small patient number and short-term results, the progression-free and overall survival in patients with OMD after local therapy for metastases and primary tumor resection following a neoadjuvant course of immunochemotherapy might be promising compared with chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: EGFR tyrosine kinase inhibitor (TKI) therapy in EGFR-mutated lung cancer is limited by acquired resistance. In half of the patients treated with first/second-generation (1st/2nd gen) TKI, resistance is associated with EGFR p.T790M mutation. Sequential treatment with osimertinib is highly active in such patients. Currently, there is no approved targeted second-line option for patients receiving first-line osimertinib, which thus may not be the best choice for all patients. The present study aimed to evaluate the feasibility and efficacy of a sequential TKI treatment with 1st/2nd gen TKI, followed by osimertinib in a real-world setting. Methods: Patients with EGFR-mutated lung cancer treated at two major comprehensive cancer centers were retrospectively analyzed by the Kaplan–Meier method and log rank test. Results: A cohort of 150 patients, of which 133 received first-line treatment with a first/second gen EGFR TKI, and 17 received first-line osimertinib, was included. Median age was 63.9 years, 55% had ECOG performance score of ≥ 1. First-line osimertinib was associated with prolonged progression-free survival (P = 0.038). Since the approval of osimertinib (February 2016), 91 patients were under treatment with a 1st/2nd gen TKI. Median overall survival (OS) of this cohort was 39.3 months. At data cutoff, 87% had progressed. Of those, 92% underwent new biomarker analyses, revealing EGFR p.T790M in 51%. Overall, 91% of progressing patients received second-line therapy, which was osimertinib in 46%. Median OS with sequenced osimertinib was 50 months. Median OS of patients with p.T790M-negative progression was 23.4 months. Conclusion: Real-world survival outcomes of patients with EGFR-mutated lung cancer may be superior with a sequenced TKI strategy. Predictors of p.T790M-associated resistance are needed to personalize first-line treatment decisions. [ABSTRACT FROM AUTHOR]

Background: This study aimed to compare local periarticular infiltration (LIA) with ultra-sound guided regional anesthesia (USRA) with ropivacaine and dexmedetomidine as an additive agent in primary total knee arthroplasty (TKA). Methods: Fifty patients were randomized into two groups in a 1:1 ratio. Patients in the LIA group received local periarticular infiltration into the knee joint. The USRA group received two single-shot USRA blocks. Functional outcomes and satisfaction (range of movement, Knee Society Knee Score, Western Ontario and McMaster Universities Osteoarthritis Index, Oxford Knee Score, and Forgotten Joint Score), including well-being, were analyzed preoperatively and at five days, six weeks, and one and two years postoperatively. Results: Functional outcomes did not significantly differ between the two groups at six weeks and one and two years after the implementation of TKA. A moderate correlation was observed in the LIA group regarding well-being and pain on day five. Six weeks postoperatively, the LIA group showed significantly superior well-being but worse pain scores. No differences between the groups in well-being and functional outcomes could be observed one and two years postoperatively. Conclusion: Patients treated with LIA had superior postoperative well-being in the early postoperative phase of up to six weeks. Furthermore, LIA patients had similar functionality compared to patients treated with USRA but experienced significantly more pain six weeks postoperatively. LIA leads to improved short-term well-being, which is potentially beneficial for faster knee recovery. We believe that LIA benefits fast-track knee recovery with respect to improved short-term well-being, higher practicability, and faster application. [ABSTRACT FROM AUTHOR]

Background: Polo like kinase 1 (PLK1) is frequently upregulated in tumors and is thus viewed as a promising therapeutic target in various cancers. Several PLK1 inhibitors have recently been developed and clinically tested in solid cancers, albeit with limited success. So far, no predictive biomarkers for PLK1 inhibitors have been established. To this end, we conducted a post-hoc biomarker analysis of tumor samples from non-small cell lung cancer (NSCLC) patients treated with the PLK1 inhibitor BI2536 in a phase II study. Methods: We analyzed formalin-fixed paraffin-embedded surplus tumor tissue from 47 study patients using immunohistochemistry (IHC) and DNA sequencing of KRAS, EGFR, BRAF, and PIK3CA. Results: KRAS-mutated patients showed numerically prolonged progression-free survival, but statistical significance was not established. Interestingly, when pathways rather than single genes were analyzed, a positive correlation between IHC staining of activated ERK (p-ERK) and mutated KRAS was detected, whereas KRAS mutation status was found to be negatively correlated with activated AKT (p-AKT). Conclusion: With this hypothesis-generating study in BI2531-treated patients, we could not establish a correlation between KRAS mutations and relevant clinical endpoints. Future clinical trials with concomitant systematic biosampling and comprehensive molecular analyses are required to identify biomarkers predictive for response to PLK1 inhibitors. [ABSTRACT FROM AUTHOR]

Background: Advanced non-small cell lung cancer (NSCLC) represents a significant unmet medical need. Despite advances with targeted therapies in a small subset of patients, fewer than 20% of patients survive for more than two years after diagnosis. Cancer vaccines are a promising therapeutic approach that offers the potential for durable responses through the engagement of the patient's own immune system. CV9202 is a self-adjuvanting mRNA vaccine that targets six antigens commonly expressed in NSCLC (NY-ESO-1, MAGEC1, MAGEC2, 5 T4, survivin, and MUC1).Methods/design: The trial will assess the safety and tolerability of CV9202 vaccination combined with local radiation designed to enhance immune responses and will include patients with stage IV NSCLC and a response or stable disease after first-line chemotherapy or therapy with an EGFR tyrosine kinase inhibitor. Three histological and molecular subtypes of NSCLC will be investigated (squamous and non-squamous cell with/without EGFR mutations). All patients will receive two initial vaccinations with CV9202 prior to local radiotherapy (5 GY per day for four successive days) followed by further vaccinations until disease progression. The primary endpoint of the study is the number of patients experiencing Grade >3 treatment-related adverse events. Pharmacodynamic analyses include the assessment of immune responses to the antigens encoded by CV9202 and others not included in the panel (antigen spreading) and standard efficacy assessments.Discussion: RNActive self-adjuvanted mRNA vaccines offer the potential for simultaneously inducing immune responses to a wide panel of antigens commonly expressed in tumors. This trial will assess the feasibility of this approach in combination with local radiotherapy in NSCLC patients.Trial Registration: Clinicaltrials.gov: NCT01915524/EudraCT No.: 2012-004230-41. [ABSTRACT FROM AUTHOR]

Percutaneous coronary intervention (PCI) in stable ischaemic heart disease (SIHD) has not been shown to improve prognosis but can alleviate symptoms and improve quality of life. Appropriately selected patients with symptoms refractory to medical therapy therefore stand to benefit, provided safety is proven. Consecutive patients undergoing PCI for SIHD between 2005–2018 in a prospective registry were included. Yearly comparisons evaluated trends, and a sub-analysis was performed comparing proximal left anterior descending artery (prox-LAD) to other-than-proximal LAD (non-pLAD) PCI. Outcomes included peri-procedural characteristics, in-hospital and 30-day event rates including MACE, and 5-year National Death Index (NDI) linked mortality. There were 9,421 procedures included. Over time, patients were increasingly co-morbid and had higher rates of AHA/ACC class B2/C lesions, ostial stenoses, bifurcation lesions, and chronic total occlusions (all p-for-trend ≤0.001). Over 14 years, major bleeding reduced (1.05% in 2005/06 vs 0.29% in 2017/18, p-for-trend <0.001), while other in-hospital and 30-day event rates were stably low. There were only seven (0.07%) in hospital deaths and 5-year mortality was 10.3%. No differences were found in outcomes between patients who underwent prox-LAD compared to non-pLAD PCI. Major independent predictors of NDI linked all-cause mortality included an eGFR <30 mL/min/1.73 m2 (HR 4.06, 95% CI 3.26–5.06), chronic obstructive pulmonary disease (COPD) (HR 2.25, 95% CI 1.89–2.67) and LVEF <30% (HR 2.13, 95% CI 1.57–2.89). Although patient and procedural complexity increased over time, a high degree of procedural success and safety was maintained, including in those undergoing prox-LAD PCI. These real-world data can enhance shared decision making discussions regarding whether PCI should be pursued in patients with symptomatic SIHD refractory to medical therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: In this short communication, we present three cases of patients with symptomatic, synchronous brain metastases of otherwise locally limited non-small cell lung cancer. The patients received local ablative treatment of the brain metastases followed by neoadjuvant immunochemotherapy with pemetrexed, cisplatin, and pembrolizumab, and resection of the pulmonary lesion with curative intent. With two of the patients still alive and maintaining a good quality of life with a progression-free survival and overall survival of 28 and 35 months, respectively, this case series illustrates the potential of novel combinatorial treatment approaches. Brain metastases are a common finding upon initial diagnosis of otherwise locally limited non-small cell lung cancer. We present a retrospective case series describing three cases of patients with symptomatic, synchronous brain metastases and resectable lung tumors. The patients received local ablative treatment of the brain metastases followed by neoadjuvant immunochemotherapy with pemetrexed, cisplatin, and pembrolizumab. Afterwards, resection of the pulmonary lesion with curative intent was performed. One patient showed progressive disease 12 months after initial diagnosis, and passed away 31 months after initial diagnosis. Two of the patients are still alive and maintain a good quality of life with a progression-free survival and overall survival of 28 and 35 months, respectively, illustrating the potential of novel combinatorial treatment approaches. [ABSTRACT FROM AUTHOR]

Background: Optimal secondary prevention pharmacotherapy is the cornerstone of post‐acute coronary syndrome (ACS) management. The prognostic impact of not receiving five guideline‐recommended therapies is poorly described. Aim: To ascertain the prognostic significance of suboptimal pharmacotherapy in ACS survivors. Methods: Consecutive patients with ACS from the Melbourne Interventional Group registry who were alive at 30 days following their index percutaneous coronary intervention were included. Patients were divided into three categories based on the number of secondary prevention medications prescribed. The optimal medical therapy (OMT), near‐optimal medical therapy (NMT), suboptimal medical therapy (SMT) groups were prescribed 5, 4 and ≤ 3 medications, respectively. Primary endpoint was long‐term mortality. Cox‐proportional hazard modelling was undertaken to assess independent predictors of survival. Results: Of the 9375 patients included, 5678 (60.6%) received OMT, 2903 (31.0%) received NMT and 794 (8.5%) received SMT. Patients receiving SMT were older, more likely to be female and had higher burden of comorbidities (renal impairment, congestive heart failure, diabetes, peripheral vascular disease; P < 0.01 for all). SMT was associated with higher long‐term mortality at 3.9 ± 2.2 years when compared to NMT and OMT (16.8% vs 10.5% vs 8.2%, P < 0.001). Compared to OMT, SMT was an independent predictor of long‐term mortality (hazard ratio, HR 1.62, 95% confidence interval, CI 1.30–2.02, P < 0.01) while NMT was associated with a clinically significant 14% mortality hazard (HR 1.14, 95% CI 0.97–1.34, P = 0.11). Conclusions: There is a graded long‐term hazard associated with not receiving OMT after an ACS. Improvements in secondary prevention pharmacotherapy models of care are warranted to further decrease the long‐term mortality. [ABSTRACT FROM AUTHOR]

Objectives: Multidrug-resistant organisms (MDRO) are considered an emerging threat worldwide. Data covering the clinical impact of MDRO colonization in patients with solid malignancies, however, is widely missing. We sought to determine the impact of MDRO colonization in patients who have been diagnosed with Non-small cell lung cancer (NSCLC) who are at known high-risk for invasive infections. Materials and methods: Patients who were screened for MDRO colonization within a 90-day period after NSCLC diagnosis of all stages were included in this single-center retrospective study. Results: Two hundred and ninety-five patients were included of whom 24 patients (8.1%) were screened positive for MDRO colonization (MDROpos) at first diagnosis. Enterobacterales were by far the most frequent MDRO detected with a proportion of 79.2% (19/24). MDRO colonization was present across all disease stages and more present in patients with concomitant diabetes mellitus. Median overall survival was significantly inferior in the MDROpos study group with a median OS of 7.8 months (95% CI, 0.0–19.9 months) compared to a median OS of 23.9 months (95% CI, 17.6–30.1 months) in the MDROneg group in univariate (p = 0.036) and multivariate analysis (P = 0.02). Exploratory analyses suggest a higher rate of non-cancer-related-mortality in MDROpos patients compared to MDROneg patients (p = 0.002) with an increased rate of fatal infections in MDROpos patients (p = 0.0002). Conclusions: MDRO colonization is an independent risk factor for inferior OS in patients diagnosed with NSCLC due to a higher rate of fatal infections. Empirical antibiotic treatment approaches should cover formerly detected MDR commensals in cases of (suspected) invasive infections. [ABSTRACT FROM AUTHOR]

Background: Stroke rates and risk factors may change as percutaneous coronary intervention practice evolves and no data are available comparing stroke incidence after percutaneous coronary intervention to the general population. Aims: This study aimed to identify the incidence and risk factors for inpatient and subsequent stroke following percutaneous coronary intervention with comparison to age-matched controls. Methods: Data were prospectively collected from 22,618 patients undergoing percutaneous coronary intervention in the Melbourne Interventional Group registry (2005–2015). The cohort was compared to the North-East Melbourne Stroke Incidence Study population-based cohort (1997–1999) and predefined variables assessed for association with inpatient or outpatient stroke. Results: Inpatient stroke occurred in 0.33% (65.3% ischemic, 28.0% haemorrhagic, and 6.7% cause unknown), while outpatient stroke occurred in 0.55%. Inpatient and outpatient stroke were associated with higher rates of in-hospital major adverse cardiovascular outcomes (p < 0.0001) and mortality (p < 0.0001), as well as 12-month mortality (p < 0.0001). Factors independently associated with inpatient stroke were renal impairment, ST-elevation myocardial infarction, previous stroke, left ventricular ejection fraction 30–45%, and female sex, while those associated with outpatient stroke were previous stroke, chronic lung disease, previous myocardial infarction, rheumatoid arthritis, female sex, and older age. Compared to the age-standardized population-based cohort, stroke rates in the 12 months following discharge were higher for percutaneous coronary intervention patients <65 years old, but lower for percutaneous coronary intervention patients ≥65 years old. Conclusions: Risk of inpatient stroke following percutaneous coronary intervention appears to be largely associated with clinical status at presentation, while outpatient stroke relates more to age and chronic disease. Compared to the general population, outpatient stroke rates following percutaneous coronary intervention are higher for younger, but not older, patients. [ABSTRACT FROM AUTHOR]

Background: Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses. Methods: We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 x 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61). Results: Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions. Conclusion: The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Purpose: Osimertinib, a third-generation irreversible mutant-selective inhibitor of EGFR kinase activity was clinically evaluated in the AURA trials, where it showed high clinical efficacy and a favorable toxicity profile in patients with acquired exon 20-EGFR pT790M mutation. We provide the clinical data of the German expanded access program that further characterizes the efficacy and safety of osimertinib in a heterogeneous patient population outside clinical trials.Methods: We performed a retrospective data analysis on patients who were included into the German osimertinib EAP.Results: Of 81 patients enrolled, 51 patients (62.9%) with sufficient case report form data were available for efficacy and safety analysis. Unconfirmed overall response rate was 80.0% with 2 patients (3.9%) achieving a complete remission and 37 patients (72.5%) having a partial remission. Disease control rate was 95.9% and only two patients showed refractory disease. Disease control rate did not correlate with clinical characteristics and was independent of number as well as type of the previous therapy line(s). Estimated progression-free survival was 10.1 months (95% CI 9.2-11.0 months). Osimertinib showed a favorable toxicity profile with no dose reductions in our observation period, even in patients with low performance status. Median survival from first diagnosis to data cut-off was 47.3 months (95% CI 43.3-51.9 months). Repeated tissue/liquid biopsy of three patients in our cohort who showed disease progression revealed an amplification of MET.Conclusions: We confirm safety and efficacy of osimertinib with high response rates among all subgroups, including patients with poor performance status and multiple prior therapy lines. Amplification of MET might mediate acquired resistance to osimertinib. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Despite the high incidence of lung cancer, little is known about distress in lung cancer survivors and patients who have survived diagnose for at least 1 year. We investigated distress prevalence and associated factors. Methods: We performed a multicenter (n = 6 hospitals) cross‐sectional study. Data were collected using medical records, questionnaires, and a telephone interview. Distress was measured with the Patient Health Questionnaire (PHQ‐4). Odds ratios (OR) for factors potentially associated with distress were calculated using multivariable logistic regression. Results: We included 561 complete case participants with a mean time since diagnosis of 4.4 years. Nineteen percent of them reported depression and 19% anxiety; 26% had 1 or both. Woman had nearly 2‐times the odds of being distressed than men (OR 1.92). Participants with UICC stage II or III at diagnosis had lower odds of being distress compared with stage I (ORs 0.41, 0.44). Participants in current treatment were less likely to be anxious or depressed than those off treatment (OR 0.32). Those with self‐reported progressing disease had 3‐times the odds of distress than people in complete remission (OR 3.00). Time since diagnosis, pain, dyspnea, lung cancer stigma as well as decreased physical functioning were related to increased distress (ORs per unit increase 0.90, 1.02, 1.03, 1.05, and 0.9, respectively). Conclusions: With a quarter of patients affected, psychological distress is a common problem in this population. Being off treatment does not imply less distress. People with poor physical functioning and pain are especially affected. Treating these symptoms is therefore very important. [ABSTRACT FROM AUTHOR]

This phase 2 portion of a phase 1/2 study examined the efficacy and safety of LY2603618, a selective checkpoint kinase 1 inhibitor, combined with pemetrexed and cisplatin (LY + Pem + Cis) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). This multicenter, randomized, controlled, open-label study (NCT01139775) enrolled patients with stage IV nonsquamous NSCLC and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized (2:1) to LY + Pem + Cis or pemetrexed and cisplatin (Pem + Cis). Induction therapy comprised four 21-day cycles of 500 mg/m 2 pemetrexed and 75 mg/m 2 cisplatin on Day 1 (both arms) and 275 mg LY2603618 on Day 2 (LY + Pem + Cis arm). Maintenance therapy comprised 500 mg/m 2 pemetrexed on Day 1 (both arms) and 275 mg LY2603618 on Day 2 (LY + Pem + Cis arm) until disease progression. The primary endpoint was progression‐free survival (PFS). Enrollment was permanently halted before target enrollment was met due to a greater number of thromboembolic events in the LY + Pem + Cis arm. Sixty-two patients were enrolled (LY + Pem + Cis, n = 39; Pem + Cis, n = 23). Bayesian and frequentist analysis demonstrated superior PFS in the LY + Pem + Cis arm vs the Pem + Cis arm (median [90% confidence interval]: LY + Pem + Cis, 4.7 months [4.–7.1]; Pem + Cis, 1.5 months [1.3–2.9]; P = 0.022). Seven patients in the LY + Pem + Cis arm (vs 0 in the Pem + Cis arm) experienced serious thromboembolic events: pulmonary embolism (n = 5), ischemic stroke (n = 1), and cerebrovascular accident (n = 1). Although the primary endpoint was met, the combination of LY2603618 + Pem + Cis will not be further developed for treating advanced nonsquamous NSCLC due to the potential increased risk of thromboembolic events with this combination. ClinicalTrials.gov Identifier: NCT01139775 . [ABSTRACT FROM AUTHOR]

Objective The cancer/testis (C/T) antigen Transmembrane Phosphatase with TEnsin homology (TPTE) is aberrantly expressed in many tumors including lung cancer. In the present study, we analyzed TPTE-auto-antibodies in lung cancer patients. Methods Using a crude-lysate ELISA, we analyzed a large cohort of 307 sera from lung cancer patients and 47 healthy donors for TPTE-specific autoantibodies. Sero-reactivity was correlated with clinical parameters and patients’ survival. Results TPTE-specific antibodies were detected in 41 of 307 (13.4%) sera from lung cancer patients. Based on an optimal cut-off value calculated by ROC curve analysis sensitivity for diagnosing lung cancer was 52% and specificity was 72%. TPTE sero-positivity was not associated with tumor stage, tumor histology, gender or age. Multivariate analysis indicated that TPTE sero-positivity is associated with prolonged survival in patients with lung cancer, but established prognostic factors for survival prediction such as stage and histology remain indispensable. Conclusion Autoantibodies against TPTE occur spontaneously in lung cancer patients. TPTE sero-reactivity has moderate sensitivity and specificity for diagnosing lung cancer and is a positive prognostic marker. [ABSTRACT FROM AUTHOR]

Background The long-term benefit of early percutaneous coronary intervention (PCI) for cardiogenic shock (CS) in elderly patients remains unclear. We sought to assess the long-term survival of elderly patients (age ≥ 75 years) with myocardial infarction (MI) complicated by CS undergoing PCI. Methods We analyzed baseline characteristics, early outcomes, and long-term survival in 421 consecutive patients presenting with MI and CS who underwent PCI from the Melbourne Interventional Group registry from 2004 to 2011. Mean follow-up of patients who survived to hospital discharge was 3.0 ± 1.8 years. Results Of the 421 consecutive patients, 122 patients were elderly (≥ 75 years) and 299 patients were younger (< 75 years). The elderly cohort had significantly more females, peripheral and cerebrovascular disease, renal impairment, heart failure (HF) and prior MI (all p < 0.05). Procedural success was lower in the elderly (83% vs. 92%, p < 0.01). Long-term mortality was significantly higher in the elderly (p < 0.01), driven by high in-hospital mortality (48% vs. 36%, p < 0.05). However, in a landmark analysis of hospital survivors in the elderly group, long-term mortality rates stabilized, approximating younger patients with CS (p = 0.22). Unsuccessful procedure, renal impairment, HF and diabetes mellitus were independent predictors of long-term mortality. However, age ≥ 75 was not a significant predictor (HR 1.2; 95% CI 0.9-1.7; p = 0.2). Conclusions Elderly patients with MI and CS have lower procedural success and higher in-hospital mortality compared to younger patients. However, comparable long-term survival can be achieved, especially in patients who survive to hospital discharge with the selective use of early revascularization. [ABSTRACT FROM AUTHOR]

Summary Background We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials. Methods Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin [LUX-Lung 3] or gemcitabine-cisplatin [LUX-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, or other) and ethnic origin (LUX-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (LUX-Lung 3) and 237 (LUX-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov , numbers NCT00949650 and NCT01121393 . Findings Median follow-up in LUX-Lung 3 was 41 months (IQR 35–44); 213 (62%) of 345 patients had died. Median follow-up in LUX-Lung 6 was 33 months (IQR 31–37); 246 (68%) of 364 patients had died. In LUX-Lung 3, median overall survival was 28·2 months (95% CI 24·6–33·6) in the afatinib group and 28·2 months (20·7–33·2) in the pemetrexed-cisplatin group (HR 0·88, 95% CI 0·66–1·17, p=0·39). In LUX-Lung 6, median overall survival was 23·1 months (95% CI 20·4–27·3) in the afatinib group and 23·5 months (18·0–25·6) in the gemcitabine-cisplatin group (HR 0·93, 95% CI 0·72–1·22, p=0·61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in LUX-Lung 3, median overall survival was 33·3 months (95% CI 26·8–41·5) in the afatinib group versus 21·1 months (16·3–30·7) in the chemotherapy group (HR 0·54, 95% CI 0·36–0·79, p=0·0015); in LUX-Lung 6, it was 31·4 months (95% CI 24·2–35·3) versus 18·4 months (14·6–25·6), respectively (HR 0·64, 95% CI 0·44–0·94, p=0·023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in LUX-Lung 3, median overall survival was 27·6 months (19·8–41·7) in the afatinib group versus 40·3 months (24·3–not estimable) in the chemotherapy group (HR 1·30, 95% CI 0·80–2·11, p=0·29); in LUX-Lung 6, it was 19·6 months (95% CI 17·0–22·1) versus 24·3 months (19·0–27·0), respectively (HR 1·22, 95% CI 0·81–1·83, p=0·34). In both trials, the most common afatinib-related grade 3–4 adverse events were rash or acne (37 [16%] of 229 patients in LUX-Lung 3 and 35 [15%] of 239 patients in LUX-Lung 6), diarrhoea (33 [14%] and 13 [5%]), paronychia (26 [11%] in LUX-Lung 3 only), and stomatitis or mucositis (13 [5%] in LUX-Lung 6 only). In LUX-Lung 3, neutropenia (20 [18%] of 111 patients), fatigue (14 [13%]) and leucopenia (nine [8%]) were the most common chemotherapy-related grade 3–4 adverse events, while in LUX-Lung 6, the most common chemotherapy-related grade 3–4 adverse events were neutropenia (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%]). Interpretation Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials. Funding Boehringer Inge [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Tigatuzumab, a humanized monoclonal DR5 agonist antibody induces apoptosis in human cancer cell lines. The objective of this study was to investigate the antitumor effects of tigatuzumab combined with carboplatin/paclitaxel in chemotherapy-naïve patients with metastatic/unresectable non-small cell lung cancer (NSCLC). Methods: Patients with histologically or cytologically confirmed NSCLC stage IIIB/IV disease by RECIST (version 1.0) and ECOG-PS 0–1 were enrolled at 15 European sites. Patients received tigatuzumab or placebo intravenously with carboplatin/paclitaxel every 3 weeks (1 cycle) for up to 6 cycles. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), objective response rate and safety. Results: 97 patients were analyzed for efficacy (49 tigatuzumab; 48 placebo). Median PFS (95% CI) was 5.4 months (3.3, 6.6) for tigatuzumab compared with 4.3 months (4.1, 5.8) for placebo. Median OS (95% CI) was 8.4 months (6.9, 16.3) for tigatuzumab versus 9.0 months (7.6, 14.5) for placebo. 12 patients (24.5%) in the tigatuzumab arm and 11 patients (22.9%) in the placebo arm had partial response. No patient had complete response. In a prospectively-defined Fc gamma receptor genotype subset (n =25), there was a non-significant trend toward increased PFS with tigatuzumab versus placebo (HR=0.47; 95% CI: 0.16, 1.35) but no difference in OS. Tigatuzumab was well tolerated. However, grade 3/4 neutropenia was reported in 10 patients (20.4%) receiving tigatuzumab compared with 4 patients (8.3%) receiving placebo. Conclusions: Tigatuzumab was well tolerated but did not improve efficacy of carboplatin/paclitaxel in systemic therapy-naïve, unselected advanced NSCLC patients. Clinical trials identifier: NCT00991796. [Copyright &y& Elsevier]

There are few data on the incidence and clinical outcomes of patients with atrial fibrillation (AF) treated in the era of percutaneous coronary intervention (PCI). We analyzed 30-day clinical outcomes in 3,307 consecutive patients with and without AF (sinus rhythm) undergoing PCI from January 2007 through December 2008 enrolled in a multicenter Australian registry. Periprocedural AF was present in 162 patients (4.9%). AF was associated with older age (74.1 ± 8.9 vs 63.9 ± 11.9 years, p <0.001), higher baseline serum creatinine (0.13 ± 0.14 vs 0.10 ± 0.13 mmol/L, p = 0.01), and lower left ventricular ejection fraction (49.5 ± 13.2% vs 53.4% ± 11.6%, p <0.001). Significantly more patients with AF had a history of heart failure and cerebrovascular and peripheral arterial diseases (p ≤0.01 for all comparisons). Periprocedural glycoprotein IIb/IIIa inhibitor (31.5% vs 31.4%, p = 0.98) and antithrombin use were not different between groups, but in-hospital bleeding complications were higher in patients with AF (5.0% vs 2.1%, p = 0.015). Fewer patients with AF received drug-eluting stents (p = 0.004). AF was associated with a greater than fourfold increase in 30-day mortality (9.9% vs 2.2%, p <0.0001) and readmission rates at 30 days (p = 0.01). Fewer patients with AF were on dual antiplatelet therapy at 30 days (86.3% vs 94.3%, p <0.0001), although 28.1% of patients with AF were on triple therapy (dual antiplatelet therapy plus oral anticoagulation). In conclusion, patients with periprocedural AF represent a very high-risk group. Excess 30-day morbidity and mortality after PCI may be due to the higher incidence of co-morbidities, bleeding complications, and suboptimal antiplatelet therapy. [ABSTRACT FROM AUTHOR]

The aim was to examine timing, causes, and predictors of death during long-term follow-up after contemporary percutaneous coronary intervention (PCI) using a large multicenter Australian registry. The cohort consisted of 10,682 consecutive patients from the Melbourne Interventional Group registry undergoing PCI (February 2004 through November 2009). For the first time in Australia, long-term mortality rates of a PCI cohort were defined by linkage to the National Death Index database. The cohort (mean age 64 ± 12 years) comprised 75% men, 24% diabetics, 59% with multivessel disease, 4.4% with renal failure, 25% with ST-elevation myocardial infarction (STEMI), 2.5% with cardiogenic shock, and 5.1% with heart failure. Drug-eluting stents (DES) were used in 43% of cases. Mean follow-up was 3.2 ± 0.5 years. In-hospital, 30-day, 12-month, and long-term (3.2 ± 0.5 years) mortalities were 1.6% (80% cardiac), 2.1% (79%), 3.9% (61%), and 8.2% (50%), respectively. Independent predictors of long-term mortality included age (hazard ratio 1.05, 95% confidence interval 1.04 to 1.06), cardiogenic shock (4.58, 3.60 to 5.83), renal failure (3.14, 2.58 to 3.82), previous heart failure (1.97, 1.60 to 2.41), STEMI (1.79, 1.47 to 2.18), peripheral vascular disease (1.72, 1.4 to 2.11), non-STEMI (1.58, 1.32 to 1.90), multivessel disease (1.47, 1.24 to 1.74), current smoking (1.39, 1.12 to 1.71), diabetes (1.36, 1.16 to 1.59), and cerebrovascular disease (1.33, 1.06 to 1.60, p <0.01 for all comparisons). DES deployment appeared protective against late mortality (hazard ratio 0.85, 0.73 to 0.99, p = 0.04); however, after 30 days, there was no difference in mortality rates between those who received a bare metal stent and those who received a DES. In conclusion, different clinical variables such as renal and heart failure predicted long-term mortality after PCI, whereas DES use in this large registry was not associated with late mortality risk. [Copyright &y& Elsevier]

Summary: MUC1 (CD227), an established tumor marker, is expressed on glandular epithelia and on epithelial tumors. Tumor MUC1 differs from normal MUC1 by modified glycan side chains. Recently, a novel carbohydrate-induced conformational tumor-associated MUC1 epitope (TA-MUC1) was described, whose clinical relevance in lung cancer is not known. Eighty-five paraffin embedded tissue sections of non-small cell lung cancer (NSCLC) patients (73% male; mean age 64±9 years) were stained with the monoclonal antibody PankoMab (against TA-MUC1) and compared with the established antibodies E29 and 214D4 regarding prognostic relevance. TA-MUC1 is virtually absent in bronchial epithelium. As shown by multivariate analysis, only staining with PankoMab, but not with E29 or 214D4, was correlated with patients’ survival (p =0.029). Moreover, when regarding interactions of MUC1 antibody staining results and clinico-pathological parameters, patients with lymph node metastasis lacking PankoMab staining were attributed the highest risk by far (Hazard ratio=4.6, 95% CI: 2.1–9.7, p =0.000). In summary, the presence of TA-MUC1 is a favorable prognostic factor in this cohort of NSCLC patients, in particular if lymph node metastases are present. This is in contrast to the results for E29 and 214D4, which recognize less or not glycosylation dependent epitopes. As this is the first report on a well-defined MUC1 epitope associated with improved survival in NSCLC, a more differentiated view on MUC1 may be mandatory. [Copyright &y& Elsevier]

Abstract: Replacement of the N-terminal β-alanyl-amide moiety in previously identified matriptase inhibitors by non-charged aryl groups caused a slightly decreased potency and partially reduced selectivity, especially towards thrombin. However, some of these analogues are still potent matriptase inhibitors with K i-values <10nM. In contrast, improved activity was observed for newly designed tribasic analogues, especially for compound 21, which inhibits matriptase with an K i-value of 80pM. [Copyright &y& Elsevier]

Abstract: Background: Restenosis rates are low in large coronary vessels ≥3.5 mm after bare-metal stent (BMS) implantation. The benefit of drug-eluting stents (DES) in large vessels is not established. Objective: We aim to assess clinical outcomes after deployment of BMS compared to DES in patients with large coronary vessels ≥3.5 mm. Methods: We analysed 672 consecutive patients undergoing percutaneous coronary interventions with ≥3.5 mm stent implantation in native coronary artery de-novo lesions from the Melbourne Interventional Group (MIG) registry. Baseline characteristics, 30-day and 12-month outcomes of patients receiving BMS were compared to DES. Multivariate analysis was performed to identify predictors of major adverse cardiac events [MACE, consisting of death, myocardial infarction (MI) and target vessel revascularisation (TVR)]. Results: Of the 672 PCIs performed in 844 lesions, DES was implanted in 39.5% (n =333) and BMS in 60.5% (n =511) of lesions. Patients who received DES compared to BMS were older, more likely to be diabetic, had left ventricular dysfunction <45% or complex lesions. Significantly fewer patients who presented with ST-elevation MI received DES compared to BMS. There were no significant differences in 12-month mortality (0.5 vs. 2.9%, p =0.07), TVR (3.6 vs. 4.8%, p =0.54), MI (6.3 vs. 3.4%, p =0.15), stent thrombosis (0.9 vs. 1.0%, p =0.88), or MACE (9.4 vs. 9.4%, p =0.90) in patients who received DES vs. BMS. Stent length ≥20 mm was the only independent predictor of 12-month MACE (Odds Ratio 2.07, 95% CI 1.14–3.76, p =0.02). Conclusion: In this registry, BMS implantation in large native coronary vessels ≥3.5 mm was associated with a low risk of MACE and repeat revascularization at 12 months that was comparable to DES. [Copyright &y& Elsevier]

Abstract: Renal impairment (RI) is known to be an independent risk factor for the progression of cardiovascular disease. Its impact, however, on the outcomes in patients undergoing percutaneous coronary intervention (PCI) especially in the era of drug-eluting stents (DES) is not well known. We analysed data from patients undergoing PCI from April 1, 2004, to September 30, 2006, who were part of the Melbourne Interventional Group registry. RI was defined as an estimated glomerular filtration rate (eGFR), calculated using Cockcroft–Gault formula, of <60 ml/min. We compared outcomes at 30 days and 12 months in patients with and without RI. Four thousand one hundred ninety-five patients (3043 male) with an average age 65±12 years (mean±S.D.) underwent PCI. Twelve-month follow-up was available in 3963 (95%) patients, and these were included in the analysis. One thousand twelve patients (26%) had RI; of these, 608 (60%) presented with an acute coronary syndrome. Both 30-day major adverse cardiac events (MACE), 9.1% vs. 4.6% (P<.01), and all-cause mortality, 4.5% vs. 0.7% (P<.01), were significantly higher in those with RI compared to those without RI. Twelve-month mortality (8.8% vs. 1.7%, P<.01) and MACE (19.7% vs. 10.3%, P<.01) were also significantly higher in those with RI. In multiple regression analysis, RI was an independent predictor of 12-month MACE [OR 2.0 (CI 1.6–2.6), P<.01]. RI is an independent predictor of 30-day and 12-month MACE and death after PCI in patients with stable and unstable coronary syndromes, even with widespread use of DES. eGFR should be used to help risk-stratify patients undergoing PCI. [Copyright &y& Elsevier]

Recent reports suggest that drug-eluting stents (DESs) may increase the risk of stent thrombosis (ST) relative to bare-metal stents (BMSs). Therefore, the aim of this study was to compare DES and BMS outcomes with a specific focus on ST. We analyzed 30-day and 1-year outcomes of 2,919 patients who underwent percutaneous coronary intervention with stent implantation from the Melbourne Interventional Group registry. Academic Research Consortium definitions of ST were used: (1) definite ST (confirmed using angiography in patients with an acute coronary syndrome), (2) probable ST (unexplained death <30 days or target-vessel myocardial infarction without angiographic confirmation), and (3) possible ST (unexplained death >30 days). Multivariate analysis was performed to identify predictors of ST. The incidence of ST (early or late) was similar between BMSs and DESs (1.6% vs 1.4%; p = 0.66), and DES use was not predictive of ST. Independent predictors of ST included the absence of clopidogrel therapy at 30 days (odds ratio [OR] 2.58, 95% confidence interval [CI] 1.29 to 5.29, p <0.01), renal failure (OR 3.30, 95% CI 1.43 to 7.59, p <0.01), index procedure presentation with an acute coronary syndrome (OR 2.59, 95% CI 1.14 to 5.87, p = 0.02), diabetes mellitus (OR 2.25, 95% CI 1.19 to 4.23, p = 0.01), and total stent length ≥20 mm (OR 1.85, 95% CI 1.00 to 3.42, p = 0.04). In conclusion, DESs were not associated with increased risk of ST compared with BMSs at 12 months in this large Australian registry that selectively used DESs for patients at high risk of restenosis. [Copyright &y& Elsevier]

• Oral Melphalan is a safe and effective treatment option in relapsed myeloid leukemia. • Patients with prior hypomethylating agent therapy seem to have additional benefit. • Melphalan is futile in patients with complex karyotype myeloid leukemia. Relapsed or refractory (R/R) disease remains challenging in acute myeloid leukemia (AML), especially in elderly patients not considered eligible for intensive treatment options. We retrospectively evaluated the safety and efficacy of low-dose melphalan (LD-Mel) in a multicenter analysis in patients over 65 years with R/R AML, who previously had received ≥1 non-curative treatment line. The study included 31 patients (median age 77 years) with 1–4 previous treatment lines. Three patients (9.7%) achieved a complete remission. Two patients (6.5%) achieved a partial remission, nine patients (29.0%) had disease stabilization with reduction of peripheral or bone marrow blast burden, resulting in an overall response rate of 16.1% and 45.2% achieved clinical benefit. Responders showed a significantly longer median overall survival than non-responders (16.3 vs. 2.3 months, p < 0.001). Multivariate analysis identified complex karyotype as the only risk factor associated with inferior survival (p < 0.001), whereas prior treatment with hypomethylating agents (HMAs) in 25 of 31 patients was associated with superior OS, regardless of prior response to HMAs (p = 0.03). LD-Mel was well tolerated, with mild myelosuppressive side effects. Conclusively, LD-Mel is an effective treatment option in elderly patients with R/R AML, particularly after HMA therapy and in the absence of a complex karyotype. [ABSTRACT FROM AUTHOR]

Background: Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses. Methods: We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61). Results: Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions. Conclusion: The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors. Trial registration: ClinicalTrials.gov identifier: NCT01915524. [ABSTRACT FROM AUTHOR]